Cell treatment slows disease in Duchenne muscular dystrophy patients


Date:
April 13, 2022
Source:
Cedars-Sinai Medical Center
Summary:
A cell therapy stabilizes weakened muscles--including the heart
muscle - - in Duchenne muscular dystrophy patients, a new study
shows.



FULL STORY ==========================================================================
A cell therapy developed by the executive director of the Smidt Heart
Institute stabilizes weakened muscles-including the heart muscle-in
Duchenne muscular dystrophy patients, a new study published in the international peer-reviewed journal The Lancetshows.


==========================================================================
If the HOPE-2 study's success is duplicated in the upcoming multicenter, randomized, placebo-controlled HOPE-3 clinical trial, the intravenous
cell therapy could become the first Food and Drug Administration-approved treatment for Duchenne patients with advanced disease.

"This therapy is unique in that it addresses two vital needs in patients
with Duchenne: physical movement and a healthy heart," said Eduardo
Marba'n, MD, PhD, executive director of the Smidt Heart Institute
at Cedars-Sinai, the Mark S. Siegel Family Foundation Distinguished
Professor, an author on the study and the inventor of cardiosphere-derived cells (CDCs), progenitor cells derived from human heart tissue, which
have been used in multiple clinical trials.

Duchenne muscular dystrophy is a rare, inherited disorder that mostly
affects males. It's caused by mutations on a gene on the X chromosome
that interferes with the production of a protein called dystrophinthat
muscles need to function. Children born with such mutations have muscle weakness throughout their bodies. This makes it difficult for them to do
normal activities like run, jump, climb stairs, stand up after sitting
and pedal a bicycle. They can also become extremely sick when muscles
in their hearts and respiratory organs weaken.

The prognosis for patients with Duchenne muscular dystrophy is bleak. Most
use a wheelchair by the time they are teenagers and don't typically live
into their 30s. There is no cure for the disease. Currently, the only
approved medical treatments are aimed at delaying loss of the ability
to walk; nothing is available for patients with more advanced disease,
who now outnumber those with milder symptoms.

"The HOPE-2 trial is a game changer for muscular dystrophy," said Craig M.

McDonald, MD, the trial's principal investigator and the professor
and chair of physical medicine and rehabilitation and professor of
pediatrics, from University of California, Davis Health, one of several
sites participating in the trial. "For the first time, we have a treatment which markedly slows loss of arm function and preserves heart function
in Duchenne patients. The cells are given intravenously, and only four
times a year, so the treatment is not burdensome for patients and their families." Other experimental therapies aim to get the body to make dystrophin. The therapy studied in this Phase II clinical trial takes a different approach. It uses heart cells called cardiospheres, or CDCs,
which are a type of progenitor cells derived from human heart tissue, to improve the function of skeletal muscle and the heart, at least partly
by blunting inflammation. Skeletal muscle mediates voluntary movement,
such as that of the arms, while the heart pumps blood throughout the
body to sustain life.



========================================================================== "This therapeutic approach makes it possible for everyone with DMD to
benefit regardless of their exact genetic mutation, which can vary from
child to child," Marba'n said. "The fact that the cells help both heart
and skeletal muscle is notable, as no other treatments have done so."
The trial was sponsored by Capricor Therapeutics, a San Diego- based biotechnology company, which holds a worldwide, exclusive license for
this technology and intellectual property and manufactures the cell
treatment under the product name of CAP-1002.

"We are extremely encouraged by the results of the HOPE-2 study," said
Linda Marba'n, PhD, Capricor's CEO. "We now have conducted HOPE-Duchenne
and HOPE-2, the Phase I and Phase II clinical trials using CAP-1002 to
treat late-stage DMD patients. These showed statistically significant improvements in upper limb and/or cardiac function in the treatment
groups. We are in the process of initiating a Phase III pivotal study,
called HOPE-3, which the FDA has signaled as the next step toward product approval for the serious unmet need of DMD." The study included 20
boys from multiple hospitals across the U.S. All were 10 or older and
all had Duchenne muscular dystrophy.

Each patient in the trial had what investigators classified as "moderate
upper limb impairment," meaning their function ranged from being able
to raise both arms simultaneously above their heads by flexing at the
elbow to being able to raise one or two hands to the mouth, but not
bring a cup to it.



========================================================================== "Children with DMD eventually become dependent on their arms for most
of their activities, such as eating and operating their wheelchair,"
McDonald said. "Any improvement in upper limb function can make a huge difference." Eight children were randomly assigned to receive the cell
therapy and 12 were randomly assigned to receive the placebo. The cells
and placebo were administered intravenously every three months for a
year. The study was double- blinded, meaning neither the doctors nor
patients knew who was getting the treatment or placebo.

Results showed patients who were given CAP-1002 experienced less loss of ability in their upper limbs after 12 months than patients who received
the placebo. Although children given CAP-1002 still lost some upper
limb movement during that period, they did so at a rate that was 71%
slower than in children who didn't receive the therapy.

Heart function also improved in children given the cell-based therapy
versus the placebo -- an important finding since heart failure is a main
cause of death in people with Duchenne muscular dystrophy.

The new Lancet study is the latest in Marba'n's body of work that
harnesses CDCs to improve heart function. Results from the earlier
CADUCEUS trial, published in The Lancet in 2014, showed that infusing CDCs
into the hearts of heart attack survivors significantly reduced their
heart attack scars. The present study uses intravenous cell delivery,
which is much easier than cardiac infusion.

The treatment appears to be safe. One child experienced a severe
allergic reaction to CAP-1002 during a second intravenous infusion and
required an injection of epinephrine and hospitalization. After that,
the investigators put the children on a pre-treatment drug regimen to
reduce the risk of allergic reactions. Only one child experienced an
allergic reaction after this was implemented, and he did not require
medication or hospitalization.

More studies are needed to learn whether the effects of this therapy
last longer than 12 months and prolong the lives of children with DMD.

"Here we show the promise of cell therapy in preventing the progression
of heart disease in a rare genetic disease, but there is good reason to
believe that such therapy may one day be used for more common forms of
heart failure," Marba'n said.


========================================================================== Story Source: Materials provided by Cedars-Sinai_Medical_Center. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Craig M McDonald, Eduardo Marba'n, Suzanne Hendrix, Nathaniel Hogan,
Rachel Ruckdeschel Smith, Michelle Eagle, Richard S Finkel, Cuixia
Tian, Joanne Janas, Matthew M Harmelink, Arun S Varadhachary,
Michael D Taylor, Kan N Hor, Oscar H Mayer, Erik K Henricson, Pat
Furlong, Deborah D Ascheim, Siegfried Rogy, Paula Williams, Linda
Marba'n, Russell Butterfield, Anne Connolly, Francesco Muntoni,
Nanette C. Joyce, Maya Evans, Mehrdad Abedi, Prasanth Surampudi,
Sanjay Jhawar, Jonathan G.

Dayan, Colleen Anthonisen, Erica Goude, Alina Nicorici, Omaid
Sarwary, Poonam Prasad, Jayoon Baek, Andrew Newton, Hannah Johnson,
Kyle Kusmik, Lauri Filar, Angie Edmondson, Irina Rybalsky, Wendy
Chouteau, Anthony F.

Giordano, Aixa Rodriguez, Kristan Anderson, Germaine Wezel, Melisa
Vega, Julie Duke, Jorge Collado, Matthew Civitello, Julie Wells,
Erika Pyzik, Rebecca Rehborg, Michelle Brown, Jennifer Van Eyk,
Russell G. Rogers.

Repeated intravenous cardiosphere-derived cell therapy in late-stage
Duchenne muscular dystrophy (HOPE-2): a multicentre, randomised,
double- blind, placebo-controlled, phase 2 trial. The Lancet,
2022; 399 (10329): 1049 DOI: 10.1016/S0140-6736(22)00012-5 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220413161733.htm

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